mitochondrial complex I deficiency, nuclear type 26

Summary

mitochondrial complex I deficiency, nuclear type 26 (MONDO:0032630) is a disease caused by NDUFA9 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: NDUFA9 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 26

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 26
Mondo ID	MONDO:0032630
OMIM	618247
DOID	DOID:0112086
UMLS	C4748809
MedGen	1648283
GARD	0025709
Is cancer (heuristic)	no

Also known as: MC1DN26

Data availability: 26 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial respiratory chain complex deficiency › mitochondrial complex I deficiency › mitochondrial complex I deficiency, nuclear type › mitochondrial complex I deficiency, nuclear type 26

Related subtypes (36): mitochondrial complex I deficiency, nuclear type 12, mitochondrial complex I deficiency, nuclear type 30, Leber hereditary optic neuropathy, autosomal recessive, mitochondrial complex I deficiency, nuclear type 36, mitochondrial complex I deficiency, nuclear type 37, mitochondrial complex I deficiency, nuclear type 2, mitochondrial complex I deficiency, nuclear type 3, mitochondrial complex I deficiency, nuclear type 4, mitochondrial complex I deficiency, nuclear type 5, mitochondrial complex I deficiency, nuclear type 6, mitochondrial complex I deficiency, nuclear type 7, mitochondrial complex I deficiency, nuclear type 8, mitochondrial complex I deficiency, nuclear type 9, mitochondrial complex I deficiency, nuclear type 10, mitochondrial complex I deficiency, nuclear type 11, mitochondrial complex I deficiency, nuclear type 13, mitochondrial complex I deficiency, nuclear type 14, mitochondrial complex I deficiency, nuclear type 15, mitochondrial complex I deficiency, nuclear type 16, mitochondrial complex I deficiency, nuclear type 17, mitochondrial complex I deficiency, nuclear type 18, mitochondrial complex I deficiency, nuclear type 19, mitochondrial complex I deficiency, nuclear type 21, mitochondrial complex I deficiency, nuclear type 22, mitochondrial complex I deficiency, nuclear type 23, mitochondrial complex I deficiency, nuclear type 24, mitochondrial complex I deficiency, nuclear type 25, mitochondrial complex I deficiency, nuclear type 27, mitochondrial complex I deficiency, nuclear type 28, mitochondrial complex I deficiency, nuclear type 29, mitochondrial complex I deficiency, nuclear type 31, mitochondrial complex I deficiency, nuclear type 32, mitochondrial complex I deficiency, nuclear type 33, mitochondrial complex I deficiency, nuclear type 34, mitochondrial complex I deficiency, nuclear type 1, mitochondrial complex I deficiency, nuclear type 39

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

26 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 6 conflicting classifications of pathogenicity, 6 pathogenic, 4 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
30391	NM_005002.5(NDUFA9):c.962G>C (p.Arg321Pro)	NDUFA9	Pathogenic	no assertion criteria provided
3375138	NM_005002.5(NDUFA9):c.895C>T (p.Arg299Ter)	NDUFA9	Pathogenic	criteria provided, single submitter
4690255	NM_005002.5(NDUFA9):c.710A>T (p.Lys237Ile)	NDUFA9	Pathogenic	no assertion criteria provided
4690256	NM_005002.5(NDUFA9):c.1069C>G (p.Arg357Gly)	NDUFA9	Pathogenic	no assertion criteria provided
4690257	NM_005002.5(NDUFA9):c.800G>T (p.Gly267Val)	NDUFA9	Pathogenic	no assertion criteria provided
4690259	NM_005002.5(NDUFA9):c.1078C>G (p.Arg360Gly)	NDUFA9	Pathogenic	no assertion criteria provided
3234875	NM_005002.5(NDUFA9):c.267T>A (p.Tyr89Ter)	NDUFA9	Likely pathogenic	criteria provided, single submitter
3895836	NM_005002.5(NDUFA9):c.552+1_552+5del	NDUFA9	Likely pathogenic	criteria provided, single submitter
4687641	NM_005002.5(NDUFA9):c.897-1G>C	NDUFA9	Likely pathogenic	criteria provided, single submitter
996908	NM_005002.5(NDUFA9):c.938G>A (p.Trp313Ter)	NDUFA9	Likely pathogenic	criteria provided, single submitter
214714	NM_005002.5(NDUFA9):c.728T>C (p.Val243Ala)	NDUFA9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214715	NM_005002.5(NDUFA9):c.942A>G (p.Ile314Met)	NDUFA9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214722	NM_005002.5(NDUFA9):c.224G>T (p.Arg75Leu)	NDUFA9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372847	NM_005002.5(NDUFA9):c.655+5G>A	NDUFA9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
587683	NM_005002.5(NDUFA9):c.1078C>T (p.Arg360Cys)	NDUFA9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
917538	NM_005002.5(NDUFA9):c.1061G>A (p.Arg354Gln)	NDUFA9	Conflicting classifications of pathogenicity	no assertion criteria provided
1030867	NM_005002.5(NDUFA9):c.251A>C (p.Tyr84Ser)	NDUFA9	Uncertain significance	criteria provided, single submitter
1201565	NM_005002.5(NDUFA9):c.223C>T (p.Arg75Cys)	NDUFA9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1806302	NM_005002.5(NDUFA9):c.50G>T (p.Arg17Leu)	NDUFA9	Uncertain significance	criteria provided, single submitter
214723	NM_005002.5(NDUFA9):c.253C>T (p.Arg85Trp)	NDUFA9	Uncertain significance	criteria provided, multiple submitters, no conflicts
2689549	NM_005002.5(NDUFA9):c.721T>C (p.Tyr241His)	NDUFA9	Uncertain significance	criteria provided, multiple submitters, no conflicts
2689550	NM_005002.5(NDUFA9):c.158G>C (p.Gly53Ala)	NDUFA9	Uncertain significance	criteria provided, single submitter
423575	NM_005002.5(NDUFA9):c.727G>A (p.Val243Ile)	NDUFA9	Uncertain significance	criteria provided, multiple submitters, no conflicts
802811	NM_005002.5(NDUFA9):c.897-115A>G	NDUFA9	Uncertain significance	criteria provided, multiple submitters, no conflicts
138448	NM_005002.5(NDUFA9):c.552+11A>C	NDUFA9	Benign	criteria provided, multiple submitters, no conflicts
138449	NM_005002.5(NDUFA9):c.553-17G>A	NDUFA9	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NDUFA9	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 26	4

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NDUFA9	HGNC:7693	ENSG00000139180	Q16795	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDUFA9	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NDUFA9	Other/Unknown	no		Epimerase_deHydtase, NAD(P)-bd_dom_sf, ComplexI_NDUFA9_subunit

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
heart left ventricle	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDUFA9	295	ubiquitous	marker	apex of heart, mucosa of transverse colon, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFA9	3,976

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDUFA9	Q16795	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Complex I biogenesis	1	165.5×	0.015	NDUFA9
Respiratory electron transport	1	95.2×	0.015	NDUFA9
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	NDUFA9
Metabolism	1	11.6×	0.086	NDUFA9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ubiquinone biosynthetic process	1	936.2×	0.004	NDUFA9
mitochondrial electron transport, NADH to ubiquinone	1	358.6×	0.004	NDUFA9
sodium ion transport	1	271.8×	0.004	NDUFA9
proton motive force-driven mitochondrial ATP synthesis	1	263.3×	0.004	NDUFA9
aerobic respiration	1	247.8×	0.004	NDUFA9
circadian rhythm	1	244.2×	0.004	NDUFA9

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NDUFA9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NDUFA9	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NDUFA9

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NDUFA9	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.